We have raised murine monoclonal antibodies (MAbs) to a conserved region of the CD4 binding site of gp120 (CD4bs) that neutralize genetically diverse HIV strains. The MAbs have a novel mechanism of action. They hydrolyze multiple molecules of gp120, thereby imparting MAb increased biological efficacy. About 10% of HIV infected subjects develop resistance to currently available drug regimens and have no other treatment options. Our MAbs are intended to fulfill this unmet medical need. In the present Phase I proposal, we will conduct molecular engineering and initial functional studies necessary to preparing therapy-grade MAbs. We will: (a) clone two chimeric MAbs (cMAbs) with reduced immunogenicity by fusing the murine catalytic variable domains to human IgG constant domains;(b) establish that the cMAbs express catalytic and epitope specificity properties comparable to the parent MAbs;(c) determine the potency with which the cMAbs neutralize genetically diverse HIV strains as the initial efficacy indicator;and (d) confirm the absence of cMAb cross-reaction with host human proteins, a requirement for a MAb designed for clinical use in humans. If the cMAbs meet the Phase I milestones, we will seek Phase II support for animal model efficacy tests, toxicity analysis and pharmacokinetic studies to enable human testing. PUBLIC HEALTH RELEVANCE: No adequate therapies are available for HIV infected patients who develop resistance to antiretroviral drugs. We will examine the feasibility of developing antibodies that degrade the coat protein of HIV for treatment of such patients.